Therapeutic Focus

HUMAN BIOLOGY PROVIDES THE ROADMAP FOR TARGET SELECTION AT JNANA.

Human genetics and patient data, brought together via innovative bioinformatics approaches, offer critical clues to targets where modulation can have a profound impact on disease progression. Jnana’s current internal focus is on immune-mediated diseases, oncology, and metabolite-dependent diseases where metabolites, as biomarkers, provide a clear translational path from preclinical studies to clinical development. With our biopharma partners, we are also working to provide first and best-in-class treatments for immune-mediated and neurological diseases. Jnana is dedicated to diseases with high unmet patient needs where target modulation can result in a novel or differentiated approach to current therapies.

IMMUNE-MEDIATED DISEASES

An immune system deficit can pre-dispose an individual to infection and cancer risk and, when uncontrolled, can give rise to inflammation and progressive organ damage. Despite progress in disease diagnosis and development of novel therapies, the burden of autoimmune and chronic inflammatory conditions remains high.

In these conditions, aberrantly activated metabolic and cellular signaling pathways affect the regulation of specific subsets of immune cells and contribute to disease. At Jnana, we have developed proprietary tools that enable us to leverage the knowledge of sentinel targets and pathways for the development of potentially transformational new therapies. Our unbiased SLC transporter-wide genetic screens in primary human immune cell subsets have revealed new targets for the potential treatment of autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease, as well as oncology. Our RAPID platform is ideally suited to efficiently drug these novel SLC targets. We are also pursuing targets from diverse gene families that have strong genetic validation but are perceived as undruggable.  We believe that RAPID has the power to unlock the potential of these high value targets to create transformational new therapies.

Oncology

Despite meaningful advances in cancer therapy, there are still many tumor types that are not adequately addressed and large patient populations with significant remaining unmet need. Jnana is focused on applying our RAPID platform to previously undruggable, highly validated oncology targets.

METABOLITE-DEPENDENT DISEASES

At Jnana, we are also interested in diseases characterized by metabolite dysregulation, where there is validated human biology connecting modulation of a target such as a solute carrier (SLC) to regulation of that metabolite. In these diseases, the metabolite concentration provides a clear translational path to the clinic, serving as a critical biomarker for patient selection and efficacy.

Jnana’s lead program is focused on phenylketonuria (PKU), in many ways the quintessential metabolite-dependent disease. PKU is a genetic disease where loss of function mutations in the liver enzyme phenylalanine hydroxylase (PAH) result in a high systemic excess of phenylalanine (Phe) which drives all neurocognitive and neuropsychiatric pathologies in these patients. Systemic levels of Phe are regulated by SLC6A19 (B0AT1), a transporter responsible for Phe reabsorption in the kidney proximal tubule. In analogy to SGLT2 (SLC5A2) inhibitors that work by blocking glucose reabsorption in the kidney proximal tubule and which have had substantial clinical impact, blocking reabsorption of Phe via inhibition of SLC6A19 will significantly lower levels of plasma Phe.1 The translational path for an SLC6A19 inhibitor in PKU patients is clear where plasma Phe is the primary registrational endpoint. This differentiated approach will lead to an oral small molecule that can be used in any PKU patient, notwithstanding age or PAH mutation, where unmet need remains high.

Another Jnana metabolite dependent disease program addresses phosphate dysregulation in Stage 3/4 chronic kidney disease (CKD). Phosphate dysregulation is a key driver of the cardiac morbidity and mortality associated with CKD. Phosphate management is well-recognized as a critical therapeutic goal; however, currently approved therapies (phosphate binders) are only effective at impacting phosphate in end-stage renal disease (ESRD) or Stage 5 CKD. Jnana’s approach to address phosphate dysregulation (again following the SGLT2 paradigm) is to inhibit a kidney proximal tubule SLC (SLC34A1) responsible for phosphate reabsorption in the kidney to increase excretion and reduce systemic levels of phosphate. Since kidney reabsorption is the central node for regulating phosphate in individuals prior to ESRD, this approach should prove highly effective.

 

Reference

1 Inhibiting Neutral Amino Acid Tranport for the Treatment of Phenylketonuria, Belanger et al., JCI Insight. 2018, 3(14).

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